Restenosis mechanism

I. The long time span from balloon angioplasty to the stent era. As we previously alluded, the restenosis mechanisms are different between angioplasty and stenting. 

Laser ablation systems hold considerable promise if restenosis (reblocking of the arteries) rates are reduced. The rate as of 1995 is 30%, typically within six months. Mechanical or atherectomy devices to cut, shave, or pulverize plaque have been tested extensively in coronary arteries. Some of these have also been approved for peripheral use. The future of angioplasty, beyond the tremendous success of conventional balloon catheters, depends on approaches that can reduce restenosis rates. For example, if appHcation of a dmg to the lesion site turns out to be the solution to restenosis, balloon catheters would be used for both dilating the vessel and deUvering the dmg. An understanding of what happens to the arterial walls, at the cellular level, when these walls are subjected to the various types of angioplasty may need to come first. 

Schwartz RS, Holmes DR, Topol EJ. The restenosis paradigm revisited an alternative proposal for cellular mechanisms. J Am Coll Cardiol 1992 20 1284-1293. 

Is homocysteine involved in the pathogenesis of restenosis An association between homocysteine and restenosis is not unlikely, given the fact that homocysteine appears to induce inflammation, impair endothelial function, and stimulate smooth muscle proliferation all these mechanisms are potentially implicated in the development of restenosis. However, the data regarding tHcy levels and the risk of restenosis after coronary angioplasty are conflicting. Some investigators found an increased risk of restenosis after PCI in patients with high plasma levels of homocysteine, especially in patients not treated with stents (70-72), whereas others did not find any increased risk either in patients with (73-75) or without stents (76). 

Our understanding of the pathological mechanisms of restenosis is constantly evolving and the targets of therapy are changing. 

Hoffmann R, Mintz GS, Dussaillant GR, et al. Patterns and mechanisms of in-stent restenosis a serial intravascular ultrasound study. Circulation 1996 94 1247-1254. 

Acute vessel recoil, chronic remodeling, and intimal hyperplasia were the mechanisms involved in this process (1-4). However, after the introduction of stents in the daily practice during interventional procedures, intimal hyperplasia became the mechanism associated in the pathophysiology of in-stent restenosis (5-9). Therefore, its prevention should be related with therapies that inhibit smooth muscle cell proliferation. 

In the past, several clinical studies with corticosteroids failed to demonstrate a significant reduction in coronary restenosis after percutaneous transluminal coronary angioplasty (35,36). However, as we mentioned previously, after balloon angioplasty, there were other mechanisms involved in the pathophysiology of coronary restenosis (such as acute wall recoil or chronic remodeling) that explained the negative results of those studies (35,36). 

As described earlier, selection of the appropriate CDD mechanism depends on the application and the nature of the drug to be delivered, The development of DES was centered on addressing the issue of restenosis occurring secondary to neointimal hyperplasia, which was the major limiting factor after BMS implantation (16-20). 

Agent (dose) Rate of restenosis (96) Postulated mechanism References... 

This chapter focuses on percutaneous transluminal coronary angioplasty (PTCA), provides a summary of the underlying immune activities of the diseased vasculature, and focuses in part on the role of immune and inflammatory mediators in the restenotic process. In addition, the mechanism of action of sirolimus, the drug used in the first successful DES for reduction of restenosis will be highlighted. Finally, the potential role for immune mediators on the overall processes of atherosclerosis will be explored. 

Initial attempts at treating or preventing restenosis focused primarily on inhibition of the proliferation of vascular SMCs (VSMCs). A series of agents successful at inhibition of SMC proliferation in vitro as well as in vivo in animal models such as carotid injury models in the rat failed to demonstrate benefit in the clinic. More recently, it has been shown in addition to effects on SMCs, that mechanical intervention also activates the recruitment and activation of immune cells. Cell signaling through cytokines, chemokines, and adhesion molecule expression results in the recruitment to the vascular wall of cells of many types, as well as their proliferation, migration, and/or maturation. 

Sirolimus has pleotropic effects on a wide variety of cell types with relevance to restenosis. The underlying mechanism of action of the compound is as an inhibitor of the cell cycle, with its principal effect on the G I to S transition (40), Importantly, sirolimus affects the numerous cell types thought to be involved in the restenotic process including cells typically resident to the vascular wall, such as SMCs, as well as those recruited from the circulation at times of injury such as immune constituents, As the complete delineation of the steps and mechanisms of restenosis remain to be determined, the benefit of sirolimus may be due to its ability to affect the multiple cell types involved. 

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